A compound of the formula (I)
wherein X is a halogen, R1 is C1-C4 alkyl, R2 is C1-C4 alkyl, a is an integer of 1-4, R3 is C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, phenyl optionally having substituent(s) or heteroaryl optionally having substituent(s) (hereinafter sometimes to be also referred to as the present compound) is useful as a therapeutic agent for ulcerative colitis and Crohn's disease (WO98/11111).
Inflammatory bowel disease is an intractable bowel disease that is developed in a neutral area of from the upper small intestine to large intestine. Particularly, Crohn's disease is observed from duodenum to small intestine, and ulcerative colitis occurs in large intestine at lower gastrointestinal tract. The present inventors found through various experiments including animal tests that, in these diseases, drug release (compound of the formula (I)) in a lesion and a direct action thereof on the inflammatory lesion are more important than the absorption of the drug into circulation from the gastrointestinal tract.
However, the present compound is a poorly soluble compound, which shows markedly low solubility particularly in the neutral area, and an extremely high dose is problematically necessary for eliciting the effect of the present compound in a conventional oral preparation. Therefore, for the effect of the present compound to be maximally provided at a low dose, dissolution rate of the drug in the neutral area should be increased and the drug needs to be released in the lesion.
While WO98/11111 discloses, as a preparation for oral administration of the present compound, a composition comprising a mixture of the present compound and additives such as sucrose, lactose, crystalline cellulose, methylcellulose, a synthetic or semi synthetic polymer, and the like, a preparation that achieves the above-mentioned objects cannot be obtained by merely admixing the present compound with such additives, because the present compound is poorly soluble.
In general, dissolution property of a poorly soluble drug is known to be improved by methods such as preparation of the drug in a fine powder, formation of a solvate, increase of surface area by adsorption to the surface of a solid, changing the crystal form (polymorphism), mixing with excipients and pulverizing the mixture, solid dispersion and the like (JP-B-59-14446, JP-A-58-183615 and the like). For example, dissolution property and the like of Griseofulvin have been improved by giving a solid dispersion by dispersing Griseofulvin in polyethylene glycol polymers, which are water-soluble polymers (J. Pharm. Sci., 60(9), 1281-1302 (1971)). In addition, a solid dispersion of polyvinylpyrrolidone and sulfathiazole (J. Pharm. Sci., 58(5), 538-549 (1969)), a solid dispersion of fisoxazole or sulfamethizole and polyvinylpyrrolidone (Chem. Pharm. Bull., 27(5), 1223-1230 (1979)), and the like have been reported. These prior art techniques aim at improving dissolution property and enhancing bioavailability.
Pharmaceutical products are required to have ensured efficacy and safety, as well as various properties satisfying the object of use. Among others, there is a high demand on a system (called DDS) for delivering a necessary amount of a drug to the objective site over a necessary period of time by suitably designing the dosage form. The invention at this time mainly aims at controlling the drug release rate from a composition, thereby to efficiently treat inflammatory bowel diseases.